Ricinoleic acid, castor oil or derivatives thereof have been employed as effective solvents or carriers for pharmaceuticals. Unfortunately such solvents have been found to have untoward side effects. For example, ricinoleic acid and castor oil and solvents containing these substances, such as Cremophor, cause vasoconstriction. It has been found that Cremophor (a derivative of castor oil and ethylene oxide) evokes a concentration-dependent increase in force development in vascular tissues, such as the jugular vein and aorta.
Cremophor EL is known for its use with an extensive array of pharmaceuticals including taxol (Rowinsky et al "Taxol: The First of the Taxanes, an Important New Class of Antitumor Agents, Seminars in Oncology, Vol. 19, No. 6 (December) 1992, 646-662), miconazole (Handbook on Injectable Drugs), echinomycin (Handbook on Injectable Drugs), teniposide (Rowinsky et al supra), vitamin K (Rowinsky et al supra), didemnin B (Rowinsky et al supra), diazepam (Lau et al, "Absorption of diazepam and lorazepam following intranasal administration", Int. J. Pharm. 54:171-174 (Sep. 1) 1989), althesin (Dye et al, Br. Med. J. 280:1353 (Jun. 7) 1980).
The side effects caused by use of solvents such as Cremophor or other solvents containing ricinoleic acid and/or castor oil or derivatives thereof may be compounded by the particular drug dissolved in or otherwise carried by such solvent.
Cyclosporine A (CsA) is a cyclic polypeptidic immunosuppressive agent that is widely used in organ transplantation and for the treatment of autoimmune disease. Unfortunately, the use of this agent is frequently associated with renal toxicity and hypertension (Myers et al, "Cyclosporine A associated chronic nephropathy", N. Eng. J. Med. 311: 699-705, 1984; Loughran et al, "Incidence of hypertension after marrow transplantation among 112 patients randomized to either CsA or methotrexate as graft-versus-host-disease prophylaxis", Br. J. Haematol. 59: 547-553, 1985). CsA has been shown to produce vasoconstriction in the isolated perfused kidney (Mehring et al, "Mechanisms of CsA-induced vasoconstriction in the isolated perfused rat kidney", Nephron 60: 447-481, 1992) and to increase the sensitivity of isolated blood vessels and cultured vascular smooth muscle cells (Lamb and Webb, "Cyclosporine A augments reactivity of isolated blood vessels", Life Sci. 40: 2571-2578, 1987; Bokenmeyer et al, "Atrial natriuretis peptide blunts the cellular effects of cyclsporine in smooth muscle", Hypertension 21: 166-172, 1993) to a variety of stimuli. Adrenergic mechanisms (Mehring et al, supra, Tronc et al, "Mechanism of hind-limb vasoconstriction due to cyclosporin A in the dog", Circ. Res. 71: 1159-1164, 1992) and increased levels of endothelin (Fogo et al, "Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity", Kidney Intl. 42: 770-774, 1992; Takeda et al, "Endothelin-1 receptor antagonist: effects on endothelin- and cyclosporine-treated mesangial cells", Kidney Int. 42: 1713-1719, 1992) have recently been proposed to play a role in the CsA-induced toxicity. When given by infusion, CsA is prepared in Cremophor and then diluted in saline prior to administration.